Retinoic acid inhibits Ca²⁺ currents and cell proliferation in a B‐lymphocyte cell line

Abstract

Using the whole-cell variation of the patch-clamp technique, we have demonstrated that retinoic acid (RA) blocks Ca channels and inhibits cell proliferation in a mouse hybridoma cell line (MHY206) derived from a fusion of murine myeloma and splenic B cells. In 25 mM external Ca, and with an Na internal solution containing aspartate, cAMP, and Mg-ATP, inward currents were activated in these cells from holding potentials more negative than -70 mV, peaked at voltage steps up to -20 mV, and were voltage-inactivated within the 125-msec duration of the pulse. With more positive pulses, outward current carried by Na ions permeating through the Ca channels were seen. Application of RA blocked both inward and outward current through the Ca channels in a dose-dependent manner, with 50% block at a concentration of around 5 x 10(-5) M. Proliferation was blocked by 75% at that concentration, and the same relation between the reduction in current and proliferation was seen throughout the concentration range. A similar reduction of Ca currents and proliferation was demonstrated with octanol, a long-chain alcohol that has recently been reported to block Ca channels. These results suggest a role for Ca channels in the proliferation of MHY206 cells and implicate blockage of these channels as contributing to the antiproliferative activity of RA.

Aberrant expression of aldehyde dehydrogenase 1A (ALDH1A) subfamily genes in acute lymphoblastic leukaemia is a common feature of T‐lineage tumours

“…Conversely, treatment with a pan-RAR agonist specifically stimulated proliferation of the T-ALL cell lines while no such stimulation occurred in the B-lineage lines within the concentration range used. These data are consistent with previous studies in humans and mice which have shown that RA is stimulatory to T lymphocyte growth (Dillehay et al, 1989;Jiang et al, 1993;Ertesvag et al, 2002;Seguin-Devaux et al, 2005;Engedal et al, 2006) but inhibitory to the growth of B lymphocytes (Bosma & Sidell, 1988;Fahlman et al, 1995;Naderi & Blomhoff, 1999), while promoting B cell differentiation (Chen et al, 2008). This provides a plausible explanation for why aberrant ALDH1A expression is almost completely restricted to ALL tumours of T cell phenotype.…”

Human neuroblastoma cell lines as models for the in vitro study of neoplastic and neuronal cell differentiation.

“…Because the K channels in these cells are unusual in that they are sensitive to both K channel blockers and to some classical Ca channel blockers (91), we have further investigated the specificity of RA blockage in other cell types. As seen in Figure 6, RA blocks T-type Ca channels in a mouse hybridoma cell line (92,93) but does not affect the K channels in human neuroblastoma cells (which are insensitive to Ca-channel blockers). Thus, the effects of RA on human lymphocyte K channels may in part be the result of an interaction with components that are shared with Ca channels, as reflected in the sensitivity of these K channels to blockage by Ca channel blockers.…”

“…The channel block by RA was reversible such that after washout, the currents were very close to control values (not shown). aEffect of RA on T-lymphocytes (89) and 206 cells (92) suggesting that blockage of the channels contributes to its antiproliferative activity (92). In contrast to the notion that RA's effects on Ca channels are nonspecific is our unpublished observation that RA has no effect on Ca channels in the rat pituitary cell line GH3 (which contains both T-type Ca channels like those in the hybridoma cells and L-type Ca channels) (94) and does not inhibit the proliferation of these cells.…”

All- trans -retinal shuts down rod cyclic nucleotide-gated ion channels: A novel role for photoreceptor retinoids in the response to bright light?

“…20). Furthermore, retinoids have been found to modulate several ion channels, including Ca 2ϩ channels (21) and K ϩ channels (22) in lymphocytes, neuronal Na ϩ channels (23), and gap junction channels in retinal horizontal cells (24,25). In photoreceptors, retinoids have been found to stimulate the ABCR transporter, apparently by acting as substrates (26), and to modulate Ca 2ϩ channels with a possible role in the regulation of neurotransmitter release (27).…”